CN115554273A - Amoxicillin and clavulanate potassium biphasic release granules for children and preparation method thereof - Google Patents
Amoxicillin and clavulanate potassium biphasic release granules for children and preparation method thereof Download PDFInfo
- Publication number
- CN115554273A CN115554273A CN202211099801.9A CN202211099801A CN115554273A CN 115554273 A CN115554273 A CN 115554273A CN 202211099801 A CN202211099801 A CN 202211099801A CN 115554273 A CN115554273 A CN 115554273A
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- Prior art keywords
- release
- granules
- amoxicillin
- enteric
- coating layer
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Links
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- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 title claims abstract description 89
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Abstract
The invention provides amoxicillin and clavulanate potassium biphasic release granules for children and a preparation method thereof. The two-phase release granule consists of a quick release granule and an enteric sustained release granule; the quick-release particles are composed of the following raw materials in percentage by mass: 75-90% of amoxicillin trihydrate and potassium clavulanate mixture, 2-10% of disintegrating agent, 5-10% of suspending agent, 0.2-5% of glidant, 0.5-2% of lubricant and 1-3% of flavoring agent; the enteric-coated sustained-release granules are prepared from the following raw materials in percentage by mass: 65-80% of a mixture of amoxicillin trihydrate and potassium clavulanate, 5-10% of a binder, 5-10% of a slow-release coating layer material and 10-20% of an enteric coating layer material; the mass ratio of the amoxicillin trihydrate in the quick-release granules to the amoxicillin trihydrate in the enteric-coated sustained-release granules is 1.
Description
Technical Field
The invention relates to amoxicillin and clavulanate potassium biphasic release granules for children and a preparation method thereof, belonging to the technical field of medicinal preparations.
Background
The amoxicillin is broad-spectrum penicillin antibiotic, the potassium clavulanate has weak antibacterial activity but strong broad-spectrum beta-lactamase inhibition effect, and the amoxicillin and the clavulanate can be used together to protect the amoxicillin from being hydrolyzed by the beta-lactamase. The amoxicillin and clavulanate potassium compound preparation has good effects on staphylococcus aureus, staphylococcus epidermidis, coagulase negative staphylococcus and enterococcus, has better antibacterial activity on enterobacteriaceae, haemophilus influenzae, moraxella catarrhalis, bacteroides fragilis and the like which produce beta-lactamase, and is increasingly popularized in clinical application.
At present, the amoxicillin and clavulanate potassium preparation is mainly an oral preparation, and comprises tablets, granules and suspensions, wherein the tablets are difficult to swallow for children groups, the granules and the suspensions are relatively easy to take, but the amoxicillin and clavulanate potassium preparation still has the difficulties of difficult medicine feeding, poor matching, easy crying and screaming and evading during medicine feeding, and forced medicine filling for adults. The market urgently needs a children preparation which has long medicine effect maintaining time, less medicine feeding times, good taste and easy swallowing.
Chinese patent document CN102861015A discloses preparation of a potassium amoxicillin clavulanate sustained-release tablet, the invention is a double-layer tablet which is respectively a quick release layer and a sustained release layer, the ratio of amoxicillin in the quick release layer and the sustained release layer is 1, clavulanic acid is totally in the quick release layer, and amoxicillin, potassium clavulanate, a filling agent, a disintegrating agent and a lubricant are subjected to dry granulation to obtain granules of the quick release layer; carrying out wet granulation and drying on amoxicillin, a slow-release material and a binding agent to obtain slow-release layer granules; and tabletting the slow release layer granules by adopting a double-layer tablet machine, adding the quick release layer granules, tabletting to obtain double-layer tablets, and coating. The invention can prolong the drug effect time and reduce the frequency of taking the medicine, but the patent still has the following defects that (1) the preparation form is a tablet which is not suitable for children to take; (2) The sustained-release part has no potassium clavulanate, the inhibition effect of the later beta-lactamase is weakened, and the antibacterial effect is influenced; (3) The sustained-release part of the medicine is gel skeleton tablet, the stomach peristalsis force is strong after meal, and the risk of burst release exists under the grinding of food.
Chinese patent document CN101890004A discloses an amoxicillin/clavulanate potassium preparation composition and a preparation method thereof: the amoxicillin, the clavulanate potassium and relevant auxiliary materials necessary for the forming of corresponding preparations are prepared into formed plain tablets or plain granules by corresponding processes, and then are coated with slow release materials to prepare slow release tablets and slow release granules; or the sustained-release material is taken as a sustained-release framework to be mixed with other auxiliary materials required by forming to prepare according to the existing granulation process, and then the mixture is prepared into granules or further tableted to obtain sustained-release granules and sustained-release tablets. The invention provides a preparation method of sustained-release granules, but still has the following defects that (1) the granules are prepared by adopting a soft material preparation granulation process or centrifugal granulation, potassium clavulanate is unstable and is easy to degrade under the wet and hot conditions, and the preparation process has a larger defect in the aspect of quality control; (2) The antibacterial preparation is generally a dose impact therapy and needs to quickly reach effective blood concentration, but the preparation of the invention is a single-phase sustained-release preparation, cannot quickly reach the effective medicine concentration, has slow effect and increases the risk of bacterial drug resistance.
Chinese patent document CN101890005A discloses a composition of amoxicillin/potassium clavulanate enteric-coated preparation and a preparation method thereof: the invention prepares enteric-coated tablets and granules by coating materials on the formed plain tablets/plain granules and pellets, and has the following defects that (1) the granules are prepared by adopting a soft material granulation process or centrifugal granulation, the potassium clavulanate is unstable and is easy to degrade under the wet and hot conditions, and the preparation process has larger defects in the aspect of quality control; (2) failure to solve the problem of multiple administrations.
Therefore, the development of the amoxicillin and clavulanate potassium sustained-release granules for children, which have the advantages of stable quality, quick response, long drug effect maintaining time and less administration frequency, has important significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides amoxicillin and clavulanate potassium biphasic release granules for children and a preparation method thereof. The two-phase release granule has the advantages of good taste, easy swallowing, quick effect, long drug effect maintaining time and less taking times, and is suitable for children to take.
The technical scheme of the invention is as follows:
a two-phase release granule of amoxicillin and clavulanate potassium for children comprises quick release granule and enteric coated sustained release granule; the quick-release particles are composed of the following raw materials in percentage by mass: 75-90% of a mixture of amoxicillin trihydrate and potassium clavulanate, 2-10% of a disintegrating agent, 5-10% of a suspending agent, 0.2-5% of a glidant, 0.5-2% of a lubricant and 1-3% of a flavoring agent; the enteric sustained-release granules are composed of the following raw materials in percentage by mass: 65-80% of mixture of amoxicillin trihydrate and clavulanate potassium, 5-10% of adhesive, 5-10% of slow release coating layer material and 10-20% of enteric coating layer material; the mass ratio of the amoxicillin trihydrate in the quick-release granules to the amoxicillin trihydrate in the enteric-coated sustained-release granules is 1.
According to the invention, the mass ratio of the anhydrous amoxicillin to the clavulanic acid in the mixture of the amoxicillin trihydrate and the potassium clavulanate in the quick-release granules or the enteric sustained-release granules is 7.
According to the invention, the disintegrant in the quick-release granules is one or the combination of more than two of carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose and croscarmellose sodium, and is further preferably carboxymethyl starch sodium and/or crospovidone; the mass percentage of the disintegrant in the immediate release granules is preferably 5%.
According to the preferable selection of the invention, the suspending agent in the quick-release granules is one or the combination of more than two of hydroxypropyl methylcellulose, povidone, sodium carboxymethylcellulose and xanthan gum, and further preferable xanthan gum and/or hydroxypropyl methylcellulose; the mass percentage of the suspending agent in the quick-release particles is preferably 6-8%.
According to the invention, the glidant in the quick release granules is colloidal silicon dioxide, and the mass percentage of the glidant in the quick release granules is preferably 0.5-1%.
According to the present invention, the lubricant in the immediate release granules is preferably one or a combination of two or more of magnesium stearate, zinc stearate, calcium stearate, and sodium stearyl fumarate, and more preferably magnesium stearate; the mass percentage of the lubricant in the quick-release particles is preferably 0.5-1%.
According to the invention, the flavoring agent in the quick-release granules is one or the combination of more than two of aspartame, sodium cyclamate, strawberry flavor, sweet orange flavor and raspberry flavor, and is further preferably sodium cyclamate and/or sweet orange flavor; the mass percentage of the flavoring agent in the quick-release granules is preferably 2%.
According to the invention, the binding agent in the enteric sustained-release granule is preferably povidone and/or hypromellose, and more preferably povidone.
According to the invention, the material of the slow-release coating layer in the enteric slow-release granule preferably comprises a slow-release material, a plasticizer and an anti-sticking agent;
further preferably, the sustained-release material is a mixture of the ewter RS100 and the ewter RL100, and the mass ratio of the ewter RS100 to the ewter RL100 in the mixture is 2;
more preferably, the plasticizer is one or a combination of more than two of polyethylene glycol, dibutyl phthalate, triethyl citrate and triacetin, and more preferably triacetin; the mass of the plasticizer is 10-20% of the total mass of the slow-release coating layer material, and the mass is more preferably 15%;
more preferably, the antisticking agent is one or the combination of more than two of talcum powder, hydrogenated vegetable oil, glyceryl behenate and stearic acid, and more preferably talcum powder; the mass of the anti-sticking agent is 20-40%, and more preferably 30% of the total mass of the slow-release coating layer material.
According to the invention, the enteric coating layer material in the enteric sustained-release granule preferably comprises an enteric material, a plasticizer and an antisticking agent;
further preferably, the enteric material is eucalyptus L100;
more preferably, the plasticizer is one or a combination of more than two of polyethylene glycol, dibutyl phthalate, triethyl citrate and triacetin, and more preferably triacetin; the mass of the plasticizer is 10-20% of the total mass of the enteric coating layer material, and the mass of the plasticizer is more preferably 15%;
more preferably, the antisticking agent is one or the combination of more than two of talcum powder, hydrogenated vegetable oil, glyceryl behenate and stearic acid, and more preferably talcum powder; the mass of the anti-sticking agent is 20-40%, and more preferably 30% of the total mass of the enteric coating layer material.
According to the invention, the preparation method of the amoxicillin and clavulanate potassium biphasic release granules for children comprises the following steps:
(1) Preparation of immediate release granules
Adding amoxicillin trihydrate, potassium clavulanate, disintegrant, suspending agent, glidant, lubricant and flavoring agent into a mixer, and uniformly mixing; adding the mixed powder into a dry-method granulator for granulation; then sieving the obtained granules, and collecting 40-100 mesh granules to obtain quick-release granules;
(2) Preparation of enteric sustained-release granules
Carrying out cutting and spraying granulation on amoxicillin trihydrate, potassium clavulanate and a binding agent at the bottom of a fluidized bed to obtain amoxicillin potassium clavulanate granules, and collecting the granules with 40-100 meshes; sequentially coating a slow-release coating layer and an enteric coating layer on the surface of the collected potassium armorine clavulanate particles to obtain enteric slow-release particles;
(3) Mixing and subpackaging
And (2) mixing the quick-release granules and the enteric-coated sustained-release granules according to the mass ratio of the amoxicillin trihydrate of 1.
Preferably, according to the present invention, the mixing conditions in step (1) are: the speed of the mixer was 25rpm and the mixing time was 10 minutes.
Preferably, according to the present invention, the granulation conditions in step (1) are: the pressure of the granulation is 4-5 KN/cm 2 The aperture of the whole grain sieve is 0.8mm x 0.75mm; the whole grain rotating speed is 200-250 rpm.
According to the invention, after the sieving in step (1), the granules which are too large and too small are recovered and granulated until the proportion of the target granules is more than 90%.
According to the invention, the caliber of the spray gun of the fluidized bed in the step (2) is preferably 0.8-1.4 mm, and more preferably 1.2mm; the caliber of the nozzle is less than 0.8mm, the risk of gun blockage is easy to occur, the caliber is more than 1.4mm, and the risk of particle agglomeration and bed collapse is easy to occur.
Preferably, in the bottom cut-spray granulation process in step (2), the binder is prepared into a binder solution with a mass fraction of 10% for use, and the solvent used is an ethanol aqueous solution with a concentration of 90-100 vol%, preferably an ethanol aqueous solution with a concentration of 95vol%; the inventor finds that the concentration of ethanol in the solvent has an important influence on the stability of amoxicillin potassium clavulanate granules, and the degradation of potassium clavulanate occurs when the concentration of ethanol in the solvent is lower than 90vol%.
According to the invention, the conditions of the bottom-cut granulation in the step (2) are preferably as follows: the air intake is 60-80 m 3 The adhesive solution is sprayed into the mixture with the flow rate of 2.2-2.5 g/min, the atomization pressure of 0.4-0.6 bar and the material temperature of 33-4 h0 ℃; further preferably, the material temperature is 35-38 ℃; the temperature of the material is lower than 33 ℃, the moisture of the material cannot be dried in time, the risk of bed collapse occurs, and the risk of degradation of potassium clavulanate occurs at the same time; the temperature of the material is higher than 40 ℃, the degradation risk of the potassium clavulanate also occurs, and the inventor optimizes the range of the temperature of the material through a preferable experiment and avoids the degradation of the potassium clavulanate.
According to the invention, after the sieving in the step (2), the granules which are too large and too small are recycled and granulated until the proportion of the target granules reaches more than 90 percent.
According to the present invention, preferably, the coating method of the sustained-release coating layer in the step (2) is: adding the slow-release coating layer material into 95vol% ethanol water solution to obtain a slow-release coating solution, wherein the concentration of the slow-release coating layer material in the slow-release coating solution is 0.08g/mL; then the air intake is 60-80 m 3 The spraying flow rate of the slow-release coating liquid is 4.0-5.0 g/min, the atomization pressure is 0.4-0.5 bar, and the material temperature is 35-38 ℃ to coat the slow-release coating layer; the preparation method of the slow-release coating solution can be characterized in that all materials of the slow-release coating layer can be directly added into an ethanol water solution; or adding the slow release material into part of the ethanol aqueous solution to obtain a solution I, adding the plasticizer and the antisticking agent into the rest part of the ethanol aqueous solution to obtain a solution II, and then adding the solution II into the solution I to obtain the slow release coating solution, wherein the proportion of the two parts of the ethanol aqueous solution is not limited.
According to the invention, the enteric coating layer in the step (2) is preferably coated by the following method: adding the enteric coating layer material into 95vol% ethanol water solution to obtain enteric coating solution, wherein the concentration of the enteric coating layer material in the enteric coating solution is 0.08g/mL; then the air intake is 60-80 m 3 The spraying flow rate of the enteric coating liquid is 4.0 to 5.0g/min, the atomization pressure is 0.4 to 0.5bar, and the enteric coating layer is coated under the conditions that the material temperature is 35 to 38 ℃. The preparation method of the enteric coating solution can be that the enteric coating layer material is directly added into the ethanol water solution; or adding enteric material into part of ethanol water solution to obtain solution III, adding plasticizer and antisticking agent into the rest ethanol water solution to obtain solution IV, and adding solution IV into solution III to obtain solution IVThe ratio of the two ethanol aqueous solutions to the enteric coating solution is not limited.
The inventor of the application finds that the fluidized bed bottom cutting and spraying granulation is beneficial to the quality stability of the potassium clavulanate; meanwhile, the inventor optimizes the bottom cutting and spraying granulation process of the fluidized bed, ensures the stability of the potassium clavulanate and reduces the degradation risk of the potassium clavulanate.
This application is not exhaustive and is prior art in this field.
The invention has the following technical characteristics and beneficial effects:
1. the amoxicillin and clavulanate potassium biphasic release granules for children comprise quick release granules and enteric sustained release granules, wherein the quick release granules are quickly released and take effect quickly; the sustained-release particles are continuously and slowly released through the sustained-release coating film, so that the blood concentration can be maintained for a longer time, and the administration times can be reduced.
2. The quick-release granules in the amoxicillin and clavulanate potassium biphase release granules for children are prepared by adopting a dry granulation process, so that the influence of damp and heat is avoided, and the product stability is good; meanwhile, the slow-release granules are granulated by cutting and spraying at the bottom of a fluidized bed, so that the water content of the granules is low in the granulating process, the drying is quick, and the problem of degradation of the potassium clavulanate in the wet granulating process is solved to a great extent; the invention optimizes the process of cutting and spraying the bottom of the fluidized bed for granulation, particularly the caliber of a spray gun of the fluidized bed, a solvent of an adhesive, the temperature of materials in granulation and the like, and avoids the degradation of the potassium clavulanate.
3. The potassium clavulanate is a beta-lactamase inhibitor, and can inhibit the hydrolysis of amoxicillin by beta-lactamase, thereby improving the blood concentration of amoxicillin. The quick-release granules and the enteric-coated sustained-release granules both contain the potassium clavulanate, so that the inhibition of the potassium clavulanate on beta-lactamase in the whole drug release process is ensured, the enzymolysis of the amoxicillin is weakened, and the antibacterial curative effect of the amoxicillin is improved.
4. The sustained release particles in the biphasic release particles are a multi-unit drug delivery system, and the coated sustained release coating film and the enteric coating film are compact, are slightly influenced by food grinding in the stomach, and have no risk of burst release.
5. The amoxicillin and clavulanate potassium two-phase release granule for children has good taste and is easy to swallow, can be taken by water or coated in jam and cheese, and is easy to accept by children.
Drawings
FIG. 1 is a graph of plasma concentration versus time for rabbits fed the amoxicillin and clavulanate potassium biphasic release granules prepared in example 1.
FIG. 2 is a graph showing the relationship between blood concentration and time of rabbits, to which the amoxicillin and potassium clavulanate sustained-release granules prepared in comparative example 6 are fed in the experimental examples.
FIG. 3 is a graph showing the relationship between blood concentration and time in rabbits after the amoxicillin and potassium clavulanate sustained release granules prepared in comparative example 7 are fed into the experimental examples.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The fluidized bed used in the examples had a lance bore of 1.2mm.
Example 1
The composition of the amoxicillin and clavulanate potassium biphasic release granules for children is shown in the following table 1:
TABLE 1
The preparation process comprises the following steps:
1. preparation of immediate release granules
Mixing amoxicillin trihydrate, potassium clavulanate, carboxymethyl starch sodium, xanthan gum, colloidal silicon dioxide, magnesium stearate, sodium cyclamate and orange flavorThe essence was added to the hopper mixer and mixed for 10 minutes at a mixing speed of 25 rpm. Adding the mixed powder into a dry granulating machine under granulating pressure of 5KN/cm 2 The aperture of the whole grain sieve mesh is 0.8mm x 0.75mm; granulating at the whole grain rotating speed of 250 rpm; sieving the granules, collecting the granules of 40-80 meshes, recovering and granulating the oversize and undersize granules until the proportion of the target granules reaches more than 90 percent, and obtaining the quick-release granules.
2. Preparation of enteric sustained-release granules
(2.1) granulating amoxicillin trihydrate and potassium clavulanate by adopting a fluidized bed bottom cutting spray method, wherein a binding agent solution is povidone k30 ethanol water solution with the mass concentration of 10wt%, and the concentration of the ethanol water solution is 95vol%; then the air inlet volume is 80m 3 And/h, spraying the adhesive solution into the mixture at the flow rate of 2.5g/min, atomizing at the pressure of 0.5bar and at the material temperature of 38 ℃, granulating, collecting granules of 40-80 meshes, recovering and granulating the oversize granules and undersize granules until the proportion of the target granules is over 90 percent, and obtaining the potassium armorine clavulanate granules.
(2.2) coating a slow-release coating layer: adding the slow-release coating layer material into 95vol% ethanol water solution to obtain a slow-release coating solution, wherein the concentration of the slow-release coating layer material in the slow-release coating solution is 0.08g/mL; then the air is supplied for 70m 3 The slow-release coating liquid is sprayed into the slow-release coating layer at the flow rate of 4.5g/min, the atomization pressure of 0.5bar and the material temperature of 38 ℃ to coat the slow-release coating layer.
(2.3) coating an enteric coating layer: adding the enteric coating layer material into 95vol% ethanol water solution to obtain enteric coating solution, wherein the concentration of the enteric coating layer material in the enteric coating solution is 0.08g/mL; at the air inlet 70m 3 The spraying flow of the enteric coating liquid is 4.5g/min, the atomization pressure is 0.5bar, and the material temperature is 38 ℃ to coat the enteric coating layer.
3. Mixing the quick-release granules and the enteric-coated sustained-release granules according to the mass ratio of amoxicillin trihydrate of 1.
Example 2
A biphasic release formulation of amoxicillin and potassium clavulanate granules for children is prepared as described in example 1, except that: in the step (2.1), the concentration of the ethanol aqueous solution for preparing the potassium amoxicillin clavulanate particles is 90vol%.
Example 3
A biphasic release formulation of amoxicillin and potassium clavulanate granules for children is prepared as described in example 1, except that: the material temperature in step (2.1) was 33 ℃.
Example 4
A biphasic release formulation of amoxicillin and potassium clavulanate granules for children is prepared as described in example 1, except that: in the step (2.1), the material temperature is 40 ℃.
Example 5
The composition of the amoxicillin and clavulanate potassium biphasic release granules for children is shown in the following table 2:
TABLE 2
The preparation process comprises the following steps:
1. preparation of immediate release granules
Adding amoxicillin trihydrate, clavulanate potassium, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, sodium cyclamate and orange flavor into a hopper mixer, and mixing for 10 minutes at the mixing speed of 25 rpm. Adding the mixed powder into a dry granulator under a granulating pressure of 5KN/cm 2 The aperture of the whole grain sieve is 0.8mm x 0.75mm; granulating at the whole grain rotating speed of 250 rpm; sieving the granules, collecting the granules between 40 meshes and 80 meshes, recovering and granulating the oversize granules and undersize granules until the proportion of the target granules reaches more than 90 percent, and obtaining the quick-release granules.
2. Preparation of enteric sustained-release granules
(2.1) carrying out cutting, spraying and granulating on amoxicillin trihydrate and potassium clavulanate by adopting the bottom of a fluidized bed, wherein the adhesive solution is povidone k30 ethanol water solution with the mass concentration of 10%; the ethanol aqueous solution is 95vol% in concentration; then the air inlet volume is 80m 3 H, binder solutionSpraying the mixture into the mixture at a flow rate of 2.5g/min, an atomization pressure of 0.5bar and a material temperature of 38 ℃ for granulation, collecting granules between 40 and 80 meshes, recovering and granulating the oversize granules and undersize granules until the proportion of the target granules reaches over 90 percent, and obtaining the potassium armonilin clavulanate granules.
(2.2) coating a slow-release coating layer: adding the slow-release coating layer material into 95vol% ethanol water solution to obtain slow-release coating liquid, wherein the concentration of the slow-release coating layer material in the slow-release coating liquid is 0.08g/mL; then the air is supplied for 70m 3 The spraying flow rate of the slow-release coating liquid is 4.5g/min, the atomization pressure is 0.5bar, and the material temperature is 38 ℃ to coat the slow-release coating layer.
(2.3) coating an enteric coating layer: adding the enteric coating layer material into ethanol water solution with the concentration of 95vol% to obtain enteric coating liquid, wherein the concentration of the enteric coating layer material in the enteric coating liquid is 0.08g/mL; at 70m of inlet air 3 And h, coating the enteric coating layer under the conditions that the spraying flow rate of the enteric coating liquid is 4.5g/min, the atomization pressure is 0.5bar and the material temperature is 38 ℃.
3. Mixing the quick-release granules and the enteric-coated sustained-release granules according to the mass ratio of amoxicillin trihydrate of 1.
Comparison of preparation of potassium Acoxiranelate granules by different process parameters of fluidized bed granulation
Comparative example 1
Comparative sample 1 was prepared by changing the ethanol aqueous solution concentration of the binder solution of the plain granules prepared in step (2.1) of example 1 from 95vol% to 85vol% according to the enteric sustained-release granule formulation of example 1.
The preparation process comprises the following steps:
performing cutting, spraying and granulating on amoxicillin trihydrate and potassium clavulanate by adopting the bottom of a fluidized bed, wherein a binding agent solution is povidone k30 ethanol water solution with the mass concentration of 10wt%, and the ethanol water solution is 85vol%; then the air inlet volume is 80m 3 Spraying the adhesive solution into the granules with the flow rate of 2.5g/min, the atomization pressure of 0.5bar and the material temperature of 38 ℃ for granulation, collecting granules between 40 and 80 meshes, recovering and granulating the granules with the overlarge size and the undersize size until the proportion of the target granules reaches more than 90 percent, and obtaining amoxicillinGranules of potassium lavulanate.
Comparative example 2
The preparation process comprises the following steps:
performing cutting, spraying and granulating on amoxicillin trihydrate and potassium clavulanate by adopting the bottom of a fluidized bed, wherein a binding agent solution is povidone k30 ethanol water solution with the mass concentration of 10wt%, and the ethanol water solution is 95vol%; then the air inlet volume is 80m 3 And/h, spraying the adhesive solution into the mixture at the flow rate of 2.5g/min, the atomization pressure of 0.5bar and the material temperature of 30 ℃ for granulation, collecting granules of 40-80 meshes, and recycling and granulating the granules of which the sizes are too large and too small until the proportion of the target granules is over 90 percent to obtain the potassium armenicillinaravate granules.
Comparative example 3
Comparative sample 3 was prepared according to the enteric sustained-release granule formulation of example 1 by changing the temperature of the material of the granules prepared in step (2.1) of example 1 from 38 ℃ to 43 ℃.
The preparation process comprises the following steps:
performing cutting, spraying and granulating on amoxicillin trihydrate and potassium clavulanate by adopting the bottom of a fluidized bed, wherein a binding agent solution is povidone k30 ethanol water solution with the mass concentration of 10wt%, and the ethanol water solution is 95vol%; then the air inlet volume is 80m 3 And h, spraying the adhesive solution into the mixture at the flow rate of 2.5g/min, the atomization pressure of 0.5bar and the material temperature of 43 ℃ for granulation, collecting granules between 40 and 80 meshes, and recovering and granulating the granules which are too large and too small until the proportion of the target granules is over 90 percent to obtain the potassium armocillin clavulanate granules.
Comparative results
The contents, related substances and properties of the plain particles of the enteric sustained-release parts of examples 1, 2, 3, 4 and 5 and the samples of comparative examples 1, 2 and 3 were measured, and are specifically shown in table 3.
TABLE 3
As can be seen from Table 3, the preparation process of the vegetarian particles of the present invention can ensure the content of amoxicillin potassium clavulanate and avoid the degradation of potassium clavulanate.
Comparison of different granulation processes for preparing plain granules
Comparative example 4
Particles of cellulose were prepared as comparative sample 4 according to example 4 of patent CN101890004A, and the specific starting materials and amounts used are shown in table 4.
TABLE 4
The preparation process comprises the following steps: respectively sieving amoxicillin, potassium clavulanate, microcrystalline cellulose, sucrose powder and magnesium stearate with a 100-mesh sieve, weighing the microcrystalline cellulose, the sucrose powder and the magnesium stearate according to the formula, uniformly mixing in a mixer, uniformly mixing with the amoxicillin and the potassium clavulanate according to an equivalent incremental method, placing in a centrifugal granulator, spraying 4% polyvinylpyrrolidone and 85% ethanol solution to prepare granules, and drying the prepared granules at 60 ℃.
Comparative example 5
Comparative sample 5 was prepared according to example 2 of patent CN101890005A, and the specific raw materials and amounts are shown in table 5.
TABLE 5
| Amoxicillin trihydrate | 286.99g (based on amoxicillin 250.00 g) |
| Potassium clavulanate | 37.21g (31.25 g calculated as clavulanic acid) |
| Lactose | 15.00g |
| Magnesium stearate | 3.00 |
| 4% polyvinylpyrrolidone 85% ethanol solution | Proper amount of |
The preparation process comprises the following steps: respectively sieving the amoxicillin trihydrate, the potassium clavulanate, the lactose and the magnesium stearate with a 120-mesh sieve, weighing the amoxicillin trihydrate, the potassium clavulanate, the lactose and the magnesium stearate according to the prescription of the micropills, uniformly mixing in a mixer, placing in a centrifugal granulator, spraying a proper amount of 4% polyvinylpyrrolidone and 85% ethanol solution to prepare the micropills, and drying the prepared micropills at 55 ℃.
Comparison results
The contents, related substances, and properties of the plain particles of the enteric sustained-release fractions of examples 1, 2, 3, 4, and 5 and the samples of comparative examples 4 and 5 were measured, and the results are shown in table 6.
TABLE 6
As can be seen from Table 6, the present inventors have found that the use of a fluidized bed bottom shear spray granulation is beneficial to the quality stability of potassium clavulanate; meanwhile, the inventor optimizes the bottom cutting and spraying granulation process of the fluidized bed, ensures the stability of the potassium clavulanate and reduces the degradation risk of the potassium clavulanate.
Comparative example 6
TABLE 7
The preparation process comprises the following steps:
1. preparation of immediate release granules
Adding amoxicillin trihydrate, potassium clavulanate, sodium carboxymethyl starch, xanthan gum, colloidal silicon dioxide, magnesium stearate, sodium cyclamate and orange flavor into a hopper mixer, and mixing for 10 minutes at the mixing rotating speed of 25 rpm. Adding the mixed powder into a dry granulator under a granulating pressure of 5KN/cm 2 The aperture of the whole grain sieve mesh is 0.8mm x 0.75mm; granulating at the whole grain rotating speed of 250 rpm; and (3) screening the granules, collecting the granules of 40-80 meshes, recovering and granulating the oversize granules and undersize granules until the content of the target granules reaches more than 90%, and obtaining the quick-release granules.
2. Preparation of enteric sustained-release granules
(2.1) carrying out cutting, spraying and granulating on amoxicillin trihydrate at the bottom of a fluidized bed, wherein the adhesive solution is povidone k30 ethanol water solution with the mass concentration of 10wt%, and the ethanol water solution is 95vol%; then the air inlet volume is 80m 3 And/h, spraying the adhesive solution into the granules with the flow rate of 2.5g/min, the atomization pressure of 0.5bar and the material temperature of 38 ℃ for granulation, collecting granules between 40 and 80 meshes, and recycling and granulating the granules which are too large and too small until the ratio of the target granules is over 90 percent to obtain the amoxicillin granules.
(2.2) coating a slow-release coating layer: adding the slow-release coating layer material into 95vol% ethanol water solution to obtain slow-release coating liquid, wherein the concentration of the slow-release coating layer material in the slow-release coating liquid is 0.08g/mL; then at 70m of inlet air 3 The slow-release coating liquid is sprayed into the slow-release coating layer at the flow rate of 4.5g/min, the atomization pressure of 0.5bar and the material temperature of 38 ℃ to coat the slow-release coating layer.
(2.3) coating an enteric coating layer: adding the enteric coating layer material into 95vol% ethanol water solution to obtain enteric coating solution, wherein the concentration of the enteric coating layer material in the enteric coating solution is 0.08g/mL; at the air inlet 70m 3 And h, coating the enteric coating layer under the conditions that the spraying flow rate of the enteric coating liquid is 4.5g/min, the atomization pressure is 0.5bar and the material temperature is 38 ℃.
3. Mixing the quick-release granules and the enteric-coated sustained-release granules according to the mass ratio of amoxicillin trihydrate of 1.
Comparative example 7
Comparative sample 7 was prepared according to the method of example 1 in patent CN102861015A, and the specific raw material formulation is shown in table 8.
TABLE 8
The preparation process comprises the following steps: the sustained-release layer adopts wet granulation, the main drug amoxicillin and the sustained-release material are uniformly mixed, then the adhesive is added for wet granulation, and the granules of the sustained-release layer are dried and granulated to obtain granules of the sustained-release layer for standby; a quick release layer: mixing amoxicillin and potassium clavulanate as main materials with adjuvants, dry granulating, drying under reduced pressure to obtain quick release layer granule, tabletting with double-layer tablet machine, adding quick release layer granule, tabletting to obtain double-layer tablet, and coating.
Test examples
The sample of example 1 of the present invention and the samples of comparative examples 6 to 7 were each fed to 6 rabbits weighing about 1.8kg at a dose of 25mg in terms of amoxicillin anhydride, and blood concentrations were measured at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 12 hours after the feeding. The results are shown in FIGS. 1-3, and it can be seen from the graphs that, in the amoxicillin blood concentration index after 4 hours, the potassium clavulanate contained in the sustained release granules in example 1 is higher than that in comparative example 6, which does not contain potassium clavulanate, and the stability between individuals of the present invention is significantly better than that in comparative example 7.
Claims (10)
1. The amoxicillin and clavulanate potassium biphasic release granule for children is characterized by consisting of a quick release granule and an enteric sustained release granule; the quick-release particles are composed of the following raw materials in percentage by mass: 75-90% of amoxicillin trihydrate and potassium clavulanate mixture, 2-10% of disintegrating agent, 5-10% of suspending agent, 0.2-5% of glidant, 0.5-2% of lubricant and 1-3% of flavoring agent; the enteric-coated sustained-release granules are prepared from the following raw materials in percentage by mass: 65-80% of mixture of amoxicillin trihydrate and clavulanate potassium, 5-10% of adhesive, 5-10% of slow release coating layer material and 10-20% of enteric coating layer material; the mass ratio of the amoxicillin trihydrate in the quick-release granules to the amoxicillin trihydrate in the enteric-coated sustained-release granules is 1.
2. The amoxicillin and potassium clavulanate biphasic release granules for children as claimed in claim 1, wherein the mass ratio of the amoxicillin trihydrate in the immediate release granules or the enteric sustained release granules to the anhydrous amoxicillin and clavulanic acid in the potassium clavulanate mixture is 7;
the disintegrant in the quick-release granules is one or the combination of more than two of carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose and croscarmellose sodium, preferably carboxymethyl starch sodium and/or crospovidone; the mass percentage of the disintegrant in the quick-release granules is preferably 5%;
the suspending agent in the quick-release particles is one or the combination of more than two of hydroxypropyl methylcellulose, povidone, sodium carboxymethylcellulose and xanthan gum, preferably xanthan gum and/or hydroxypropyl methylcellulose; the mass percentage of the suspending agent in the quick-release particles is preferably 6-8%;
the glidant in the quick release particles is colloidal silicon dioxide, and the mass percentage of the glidant in the quick release particles is preferably 0.5-1%;
the lubricant in the quick-release granules is one or the combination of more than two of magnesium stearate, zinc stearate, calcium stearate and sodium stearyl fumarate, preferably magnesium stearate; the mass percentage of the lubricant in the quick-release particles is preferably 0.5-1%;
the flavoring agent in the quick-release granules is one or a combination of more than two of aspartame, sodium cyclamate, strawberry flavor, sweet orange flavor and raspberry flavor, preferably sodium cyclamate and/or sweet orange flavor; the mass percentage of the flavoring agent in the quick-release granules is preferably 2%.
3. The amoxicillin and clavulanate potassium biphasic release granules for children as claimed in claim 1, wherein the binder in the enteric sustained release granules is povidone and/or hypromellose, preferably povidone;
the slow release coating layer material in the enteric slow release granule comprises a slow release material, a plasticizer and an anti-sticking agent;
preferably, the sustained-release material is a mixture of the Ewing RS100 and the Ewing RL100, and the mass ratio of the Ewing RS100 to the Ewing RL100 in the mixture is 2;
preferably, the plasticizer is one or a combination of more than two of polyethylene glycol, dibutyl phthalate, triethyl citrate and triacetin, and is further preferably triacetin; the mass of the plasticizer is 10-20% of the total mass of the slow-release coating layer material, and the preferable mass is 15%;
preferably, the antisticking agent is one or the combination of more than two of talcum powder, hydrogenated vegetable oil, glyceryl behenate and stearic acid, and the talcum powder is further preferred; the mass of the anti-sticking agent is 20-40% of the total mass of the slow-release coating layer material, and more preferably 30%.
4. The amoxicillin and clavulanate potassium biphasic release granule for children as claimed in claim 1, wherein the enteric coating layer material in the enteric sustained release granule comprises enteric material, plasticizer and antisticking agent;
preferably, the enteric material is yutecqi L100;
preferably, the plasticizer is one or a combination of more than two of polyethylene glycol, dibutyl phthalate, triethyl citrate and triacetin, and is further preferably triacetin; the mass of the plasticizer is 10-20% of the total mass of the enteric coating layer material, and the preferable mass is 15%;
preferably, the antisticking agent is one or a combination of more than two of talcum powder, hydrogenated vegetable oil, glyceryl behenate and stearic acid, and the talcum powder is further preferred; the mass of the anti-sticking agent is 20-40% of the total mass of the enteric coating layer material, and more preferably 30%.
5. A process for the preparation of a biphasic release formulation of amoxicillin and potassium clavulanate for children according to any of claims 1 to 4 comprising the steps of:
(1) Preparation of immediate release granules
Adding amoxicillin trihydrate, potassium clavulanate, a disintegrating agent, a suspending agent, a glidant, a lubricant and a flavoring agent into a mixer, and uniformly mixing; adding the mixed powder into a dry-method granulator for granulation; then sieving the obtained granules, and collecting 40-100 mesh granules to obtain quick-release granules;
(2) Preparation of enteric sustained-release granules
Carrying out cutting and spraying granulation on amoxicillin trihydrate, potassium clavulanate and a binding agent at the bottom of a fluidized bed to obtain amoxicillin potassium clavulanate granules, and collecting the granules with 40-100 meshes; sequentially coating a slow-release coating layer and an enteric coating layer on the surface of the collected potassium armorine clavulanate particles to obtain enteric slow-release particles;
(3) Mixing and subpackaging
And (2) mixing the quick-release granules and the enteric-coated sustained-release granules according to the mass ratio of the amoxicillin trihydrate of 1.
6. The process for preparing amoxicillin and clavulanate potassium biphasic release granules for children according to claim 5, wherein the mixing conditions in step (1) are as follows: the rotating speed of the mixer is 25rpm, and the mixing time is 10 minutes;
the granulation conditions were: the granulating pressure is 4-5 KN/cm 2 The aperture of the whole grain sieve is 0.8mm x 0.75mm; the whole grain rotating speed is 200-250 rpm.
7. The process for preparing amoxicillin and clavulanate potassium biphasic release granules for children according to claim 5, wherein the spray gun caliber of the fluidized bed in the step (2) is 0.8-1.4 mm, preferably 1.2mm;
in the process of bottom cutting and spraying granulation, the adhesive is prepared into an adhesive solution with the mass fraction of 10% for use, and the used solvent is an ethanol water solution with the concentration of 90-100 vol%, preferably an ethanol water solution with the concentration of 95 vol%.
8. The process for preparing amoxicillin and clavulanate potassium biphasic release granules for children according to claim 5, wherein the conditions of the bottom cut spray granulation in step (2) are as follows: the air intake is 60-80 m 3 The adhesive solution is sprayed into the mixture with the flow rate of 2.2-2.5 g/min, the atomization pressure of 0.4-0.6 bar and the material temperature of 33-40 ℃; further preferably, the temperature of the material is 35 to 38 ℃.
9. The method for preparing amoxicillin and clavulanate potassium biphasic release granules for children according to claim 5, wherein the slow release coating layer in the step (2) is coated by the following method: adding the slow-release coating layer material into 95vol% ethanol water solution to obtain slow-release coating liquid, wherein the concentration of the slow-release coating layer material in the slow-release coating liquid is 0.08g/mL; then the air inlet volume is 60-80 m 3 H, spraying the slow-release coating liquid at the flow rate of 4.0-5.0 g/min, atomizing at the pressure of 0.4-0.5 bar, and coating the slow-release coating layer at the material temperature of 35-38 ℃.
10. The method for preparing amoxicillin and clavulanate potassium biphasic release granules for children as claimed in claim 5, wherein the enteric coating layer in the step (2) is coated by: adding the enteric coating layer material into 95vol% ethanol water solution to obtain enteric coating solution, wherein the concentration of the enteric coating layer material in the enteric coating solution is 0.08g/mL; then the air intake is 60-80 m 3 The spraying flow rate of the enteric coating liquid is 4.0 to 5.0g/min, and the mixture is atomizedThe pressure is 0.4 to 0.5bar, and the material temperature is 35 to 38 ℃ to coat the enteric coating layer.
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| WO1995020946A1 (en) * | 1994-02-04 | 1995-08-10 | Smithkline Beecham Plc | Bilayered amoxycillin tablets |
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